PROJECT SUMMARY The integrity of the vasculature in general and the blood-brain barrier (BBB) in particular, is of critical importance both for prevention of edema due to inflammation and injury and for targeted treatment of CNS pathologies. The ability to open BBB ?on demand? and to restore its integrity when damaged, has long been a holy grail for therapeutics. Yet the progress has been slow due to very limited understanding of mechanisms controlling BBB integrity. Indeed, no drugs currently exist that can regulate vascular permeability or BBB function. Preliminary studies from our laboratories have identified two novel, druggable pathways that selectively regulate these processes. We will define molecular basis of these novel permeability-regulating pathways, determine their biological role and develop and test therapeutic applications based on this knowledge. In particular, we propose to test a new antibody-based approach to the reduction of brain edema in acute ischemic stroke and another antibody based approach to on demand increase in the blood-brain barrier permeability sufficient to allow delivery of drugs to the brain.